B lymphocytes are the central component of the humoral immune response and malignant B lymphocytes represent the primary cell type in leukemia and lymphoma. Although B cell function is regulated through cell-surface molecules, little is known about the function and signal transduction pathways of most B cell-surface proteins other than the B cell antigen receptor (BCR) complex. The aim of this project is to further examine the function of CD19, a B lymphocyte cell-surface receptor that is a central component of a signal transducing complex that includes CD21, a receptor for the C3d complement fragment. We propose that CD19 is a cell-surface "response regulator" which controls transmembrane signals and thereby regulates signal transduction thresholds governing most B cell functions. There are three specific aims designed to test this hypothesis and to further our knowledge of how CD19 regulates signaling thresholds in B cells. In specific aim 1, we will dissect how CD 19 regulates signal transduction in vivo using CD19-deficient and CD19-overexpressing mice that we have generated. Alterations in CD19 and BCR signal transduction pathways will be assessed in B cells from these mice. We will also determine the cytoplasmic regions of CD19 that are required for intermolecular associations between signaling molecules, and assess the functional importance of these events in vivo. In specific aim 2, the extent that CD19 function is regulated in vivo by its association with CD21 will be determined. Specifically, a requirement for CD19/CD21 ligation by the C3d complement fragment will be evaluated in vivo using CD19-deficient or overexpressing mice that lack either C3 or CD21/35 expression. In specific aim 3, CD19-deficient and CD19-overexpressing mice will be used to assess how altered B cell signal transduction thresholds affect negative clonal selection in the bone marrow, peripheral tolerance, antibody repertoire selection, autoimmunity, and the development of malignant B cells. Our preliminary studies demonstrate that alterations in CD19 expression have dramatic effects on tolerance and repertoire selection. The mechanisms by which these changes are induced will be examined. Since the CD19/CD21 complex provides an important functional link between the innate and acquired immune responses, understanding CD19 function and regulation may provide mechanisms by which innate and humoral immunity can be modulated. Determining how these B cell-restricted proteins regulate B cell function may also provide new methods for treatment of B cell malignancies, autoimmunity and immunodeficiency.